Chemical synapses are connections between neurons in the human central nervous system that are fundamental to its development and normal function. At these points of nerve cell - nerve cell interaction, a chemical transmitter released from one cell diffuses across a small space, called the synapse, to receptors located on the opposing cell, triggering the opening of ligand-gated ion channels and the activation of other cell surface receptors. At excitatory synapses, the opening or activation of ligand-gated ion channels causes the influx of primarily sodium and calcium ions, depolarizing the cell and injecting a potent calcium signal. The activation and modulation of ligand- gated ion channels is thus a crucial component of signal transmission in the central nervous system. In this grant application, I propose to study the atomic structure of ionotropic glutamate receptors and acid sensing ion channels, two ubiquitous and important classes of ligand-gated ion channel. In the proposed experiments on essential fragments of the receptors, as well as on the intact receptors, I will define the precise atomic structure of these ligand-gated ion channels and will determine mechanisms of ion channel activation, inhibition and modulation. The proposed studies will reveal basic principles of ligand-gated ion channel function and they will also provide crucial molecular blueprints to guide the development of new pharmacological agents to treat debilitating diseases of the human nervous system.